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Severe sickle cell anemia is associated with increased plasma levels of TNF-R1 and VCAM-1.

ABSTRACT: Sickle cell anemia (SCA, HBB glu6val) is characterized by multiple complications and a high degree of phenotypic variability: some subjects have only sporadic pain crises and few acute hospitalizations, while others experience multiple serious complications, high levels of morbidity, and accelerated mortality [1]. The tumor necrosis factor-? (TNF-?) signaling pathway plays important roles in inflammation and the immune response; variation in this pathway might be expected to modify the overall severity of SCA through the pathway's effects on the vascular endothelium [2,3]. We examined plasma biomarkers of TNF-? activity and endothelial cell activation for associations with SCA severity in 24 adults (12 mild, 12 severe). Two biomarkers, tumor necrosis factor-? receptor-1 (TNF-R1) and vascular cell adhesion molecule-1 (VCAM-1) were significantly higher in subjects with severe SCA. Along with these biomarker differences, we also examined data from a genome-wide association study (GWAS) using SCA severity as a disease phenotype, and found evidence of genetic association between disease severity and a single nucleotide polymorphism (SNP) in VCAM1, which codes for VCAM-1, and several SNPs in ARFGEF2, a gene involved in TNF-R1 release [4].

SUBMITTER: Dworkis DA

PROVIDER: S-EPMC3078643 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Severe sickle cell anemia is associated with increased plasma levels of TNF-R1 and VCAM-1.

Dworkis Daniel A DA Klings Elizabeth S ES Solovieff Nadia N Li Guihua G Milton Jacqueline N JN Hartley Stephen W SW Melista Efthymia E Parente Jason J Sebastiani Paola P Steinberg Martin H MH Baldwin Clinton T CT

American journal of hematology 20110201 2

Sickle cell anemia (SCA, HBB glu6val) is characterized by multiple complications and a high degree of phenotypic variability: some subjects have only sporadic pain crises and few acute hospitalizations, while others experience multiple serious complications, high levels of morbidity, and accelerated mortality [1]. The tumor necrosis factor-α (TNF-α) signaling pathway plays important roles in inflammation and the immune response; variation in this pathway might be expected to modify the overall s ...[more]

PMID: 21264913

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Project description:BACKGROUND:Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea. OBJECTIVES:We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010. METHODS:An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648. RESULTS:Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003-1.006, p<0.0.0001), kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00-1.27, p = 0.043), and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23-4.02, p = 0.0082). Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34-0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17-0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels. CONCLUSIONS:Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings.

Dataset Information

Severe sickle cell anemia is associated with increased plasma levels of TNF-R1 and VCAM-1.

Publications

Severe sickle cell anemia is associated with increased plasma levels of TNF-R1 and VCAM-1.

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